Along with reports of the increasing prevalence of antiviral drug resistance among HIV, cytomegalovirus, varicella-zoster virus and influenza isolates there has been an alarming increase in clinically-significant infections due to acyclovir-resistant herpes simplex virus (HSV) in patients with HIV infection. Although the results of susceptibility testing are invariably used to guide the chemotherapeutic management of these patients, little systematic information is available to the clinician regarding the interpretation of results of these tests, as the testing methods and susceptibility breakpoints are neither standardized nor based on extensive clinical correlations. We propose to rationalize antiviral susceptibility testing of HSV by: 1. Comparing the methods currently used to test HSV for susceptibility to antivirals, 2. Correlating the results of susceptibility testing with the outcome of chemotherapy, and 3. Prospectively evaluating the test criteria in clinical trials of new and existing antivirals. The results of these studies will place susceptibility testing of HSV on the same rational footing as testing of bacteria for susceptibility to antibacterial agents.